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DNA-methylation-mediated silencing of miR-486-5p promotes colorectal cancer proliferation and migration through activation of PLAGL2/IGF2/β-catenin signal pathways.

ABSTRACT: As one of the most common cancers worldwide, colorectal cancer (CRC) causes a large number of mortality annually. Aberrant expression of microRNAs (miRNAs) is significantly associated with the initiation and development of CRC. Further investigations regarding the regulatory mechanism of miRNAs is warranted. In this study, we discovered that miR-486-5p was remarkably downregulated in CRC, which partially results from higher DNA methylation in the promoter region detected by using methylation-specific PCR, bisulfite sequencing PCR, and DNA demethylation treatment. Besides, decreased miR-486-5p was obviously associated with advanced TNM stage, larger tumor size, lymphatic metastasis, and poor prognosis in CRC. Upregulated miR-486-5p inhibited the proliferation and migration of CRC through targeting PLAGL2 expression and subsequent repressing IGF/β-catenin signal pathways both in vitro and in vivo. Notably, plasma miR-486-5p expression was significantly upregulated in CRC patients and we identified plasma miR-486-5p as a novel diagnostic biomarker of CRC using receiver operating characteristic (ROC) curve analysis. Moreover, exploration in GEO dataset revealed that circulating miR-486-5p is tumor derived through being packaged into secretory exosomes. Taken together, our data demonstrated that miR-486-5p promotes colorectal cancer proliferation and migration through activation of PLAGL2/IGF2/β-catenin signal pathway, which is a promising therapeutic target of CRC treatment.

SUBMITTER: Liu X

PROVIDER: S-EPMC6180105 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThis study aimed to describe the mechanism of exosome-derived miR-486-5p underlying the cell cycle and progression in lung adenocarcinoma (LUAD).MethodsBioinformatics methods were applied for identifying the differentially expressed genes (DEGs) in the GEO-LUAD dataset, predicting where the potential target miRNA was expressed and exploring the corresponding downstream target mRNA. qRT-PCR was conducted to detect the levels of the target genes in cancer cells. Thereafter, a series of in vitro experiments were performed for cell activities evaluation, including CCK-8, EdU, colony formation assay and transwell. Besides, Western blot was applied to determine the protein levels of the migration and invasion-related factors (NEK2, E-cadherin, N-cadherin, Vimentin, MMP-2, and MMP-9). Dual-luciferase reporter gene assay was employed for validating the targeted relationship between the target genes. Furthermore, nude mouse transplantation tumor experiment was conducted to further validate the role of the target miRNA in tumor development, and immunohistochemistry was used for Ki67 detection and TUNEL was applied for cell apoptosis assay.ResultsmiR-486-5p was observed to be enriched in serum exosomes, and seen to be significantly down-regulated in cancer tissues as well as in cancer serum exosomes. It was proven that exosomes could release miR-486-5p, thus regulating LUAD progression and affecting cell cycle. Moreover, NEK2 was identified as a target of miR-486-5p both in vivo and in vitro. Enrichment analysis revealed that NEK2 was mainly activated in cell cycle and mitosis-related pathways. Meanwhile, NEK2 was found to present significant difference in different TNM stages. Furthermore, rescue experiments indicated that the inhibitory effect of miR-486-5p overexpression on LUAD progression could be abrogated when miR-486-5p and NEK2 were simultaneously up-regulated.ConclusionExosome-derived miR-486-5p is responsible for cell cycle arrest as well as the inhibition of cell proliferation and metastasis in LUAD via targeting NEK2.

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DNA-methylation-mediated silencing of miR-486-5p promotes colorectal cancer proliferation and migration through activation of PLAGL2/IGF2/β-catenin signal pathways.

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